The Ophthalmology Department at Emory University leads a multidisciplinary collaboration with the Georgia Institute of Technology, University of Nebraska, and University of Pennsylvania. This collaboration was formed to improve drug delivery to the posterior segment of the eye. Drug delivery to this target is a significant challenge in the treatment of retinal disorders. Methods for drug treatment of the globe include systemic administration, eye drops, and injection into the orbit. Drug dilution, ocular infection, endophthalmitis, and surgical damage such as retinal detachment can occur with these techniques. Given these drawbacks, we hypothesize that transscleral approaches are better for posterior segment drug delivery. We propose to develop novel transscleral drug delivery approaches that use nanoparticles, microneedles, fibrin sealant, ontophoresis, and electoporation. We will a) examine the physiology of transscleral drug transport, b) establish analytical methods to determine the distribution of low molecular weight drugs as well as macromolecules to the various regions of the posterior segment, and c) demonstrate delivery and therapeutic effectiveness in experimental animal models. The drugs to be tested are known to affect retinal diseases in basic science experiments, pre-clinical studies, or clinical studies. This project entails collaborative research among investigators from various disciplines including ophthalmology, engineering, and pharmaceutical sciences. Milestones: Theoretical models will be completed during the first year;these will be post-experimentally reassessed annually. Drug delivery systems are established in vitro already, and during the first year will produce data sets for model refinement and establish starting parameters for in vivo studies in the first and second years. Toxicity studies will be completed during the second and third years. Pharmacokinetic and pharmacodynamic data will be collected during the third through fifth years. In the fourth and fifth years efficacy data are obtained. By accomplishing these pre-clinical tests, we will discover and develop new routes for efficacious delivery of drugs to the eye. These delivery techniques should be safer and more effective than the state of the art. Ultimately, these results will guide us in enhancing drug treatments in ophthalmic practice.